This invention relates to gene delivery. More particularly, this invention relates to nonviral gene delivery carriers.
Gene therapy has broad potential in treatment of human genetic and acquired diseases through the delivery and application of therapeutic gene-based drugs. The use of safe, efficient and controllable gene carriers is a requirement for the success of clinical gene therapy. R. C. Mulligan, The basic science of gene therapy, 260 Science 926-932 (1993); I. M. Verma & N. Somia, Gene therapy-promises, problems and prospects, 389 Nature 239-242 (1997). Although viral vectors are very efficient in gene delivery, their potential safety and immunogenicity concerns raise their risk in clinical applications. C. Baum et al., Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors, 17 Hum. Gene Ther. 253-263 (2006). As an alternative to viral vectors, cationic polymers such as poly(L-lysine) (PLL), poly(ethylenimine) (PEI), poly(amidoamine) dendrimers, and cationic liposomes have been synthesized as gene delivery carriers. The advantages of these cationic polymer carriers include safety, stability, large DNA and RNA loading capacity, and easy and large-scale production. S. Li & L. Huang, Nonviral gene therapy: promises and challenges, 7 Gene Ther. 31-34 (2000); F. Liu et al., Non-immunostimulatory nonviral vectors, 18 Faseb J. 1779-1781 (2004); T. Niidome & L. Huang, Gene therapy progress and prospects: nonviral vectors, 9 Gene Ther. 1647-1652 (2002). The cationic polymers can condense negatively charged DNA into nanosized particles through electrostatic interactions, and the polymer/pDNA polyplexes can enter cells via endocytosis. Y. W. Cho et al., Polycation gene delivery systems: escape from endosomes to cytosol, 55 J. Pharm. Pharmacol. 721-734 (2003); L. De Laporte et al., Design of modular non-viral gene therapy vectors, 27 Biomaterials 947-954 (2006); E. Piskin et al., Gene delivery: intelligent but just at the beginning, 15 J. Biomater. Sci. Polym. Ed. 1182-1202 (2004). As a result, the polymers can protect pDNA from nuclease degradation and facilitate cellular uptake to induce high gene transfection. O. Boussif et al., A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine, 92 Proc. Nat'l Acad. Sci. USA 7297-7301 (1995); D. W. Pack et al., Design and development of polymers for gene delivery, 4 Nat. Rev. Drug. Discov. 581-593 (2005).
The currently available cationic polymers, however, have significant cytotoxicity concerns, mostly due to their poor biocompatibility and non-degradability under physiological conditions.
Therefore, while prior nonviral gene delivery carriers are known and are generally suitable for their limited purposes, they possess certain inherent deficiencies that detract from their overall utility in gene therapy.
In view of the foregoing, it will be appreciated that providing improved carriers to enhance nucleotide delivery would be a significant advancement in the art.